The long term objective of this grant is to understand the role of the indoor environment in asthma. The importance of these studies comes from the prevalence of the disease, (almost 6% of the population are on treatment) and the fact that very large numbers of children and adults require treatment in emergency rooms or hospitals. The studies proposed will increase our understanding of the relevance to asthma of allergen proteins and of other constituents of the particles that become airborne. A major question has been raised by evidence that quantitatively high domestic exposures, to proteins derived from cat or dog are not associated with increased prevalence or titer of IgE antibodies (ab). By contrast, exposure to dust mite, cockroach or pollen allergens can induce sufficient IgE ab to make an important contribution to total serum IgE. This suggests that specific allergens can exert a different effect on the development of allergic disease. The novel immune response induced by cat exposure is characterized by high titer IgG and IgG4 ab without an IgE ab response. This has been described as a modified Th2 response. Interestingly it appears that the allergens that can induce this or other forms of tolerance i.e. cat, dog, mouse and rat, are all mammalian in origin. The experiments proposed will focus on: 1) Measurements of IgG and IgG4 ab, as well as total serum IgE and IgE ab to allergens in cohorts of children and adults living in different environments. These studies will investigate whether the response to mite and cat should be seen as representative of two classes of allergens; non-mammalian (Class I) and mammalian (Class II); 2) Comparison of IgE responses to protein allergens with the newly identified responses to a carbohydrate epitope on mammalian proteins that is associated with anaphylaxis but not with asthma. 3) Detailed studies on the constituents of the allergen-bearing particles that become airborne, including analysis of allergen content, as well as quantification of endotoxin and DNA derived either from the source of the allergen or from bacteria. These studies will be combined with studies on the effects of protein and non-protein (i.e. DNA or endotoxin) constituents on dendritic cells and T cells; 4) Investigation of subjects who have lived in a house with a cat without symptoms to understand a) the inflammatory and cytokine response to high exposure in children with or without IgE ab, b) the effects of a prolonged decrease of exposure to cat allergens on antibodies and T cells responses; studies that are designed to understand whether tolerant responses are dependent on continued high exposure. Overall the studies are designed to answer how differences in the indoor environment can contribute to sensitization, total serum IgE, the prevalence of asthma and the severity of this disease. The previous and proposed studies related to this grant are designed to understand the role of the indoor environment in asthma. This includes detailed investigation of the reasons why high exposure to some allergens e.g. cat and dog have less effect than high exposure to proteins and particles derived from non- mammalian allergens such as dust mites, cockroaches, or pollens. These studies are relevant to understanding the reasons why the disease is so common and to developing new approaches to treatment.